Sublingual Immunization of Trivalent Human Papillomavirus DNA Vaccine in Baculovirus Nanovector for Protection against Vaginal Challenge

Abstract

Here, we report the immunogenicity of a sublingually delivered, trivalent human papillomavirus (HPV) DNA vaccine encapsidated in a human endogenous retrovirus (HERV) envelope-coated, nonreplicable, baculovirus nanovector. The HERV envelope-coated, nonreplicable, baculovirus-based DNA vaccine, encoding HPV16L1, -18L1 and -58L1 (AcHERV-triHPV), was constructed and sublingually administered to mice without adjuvant. Following sublingual (SL) administration, AcHERV-triHPV was absorbed and distributed throughout the body. At 15 minutes and 1 day post-dose, the distribution of AcHERV-triHPV to the lung was higher than that to other tissues. At 30 days post-dose, the levels of AcHERV-triHPV had diminished throughout the body. Six weeks after the first of three doses, 1×108 copies of SL AcHERV-triHPV induced HPV type-specific serum IgG and neutralizing antibodies to a degree comparable to that of IM immunization with 1×109 copies. AcHERV-triHPV induced HPV type-specific vaginal IgA titers in a dose-dependent manner. SL immunization with 1×1010 copies of AcHERV-triHPV induced Th1 and Th2 cellular responses comparable to IM immunization with 1×109 copies. Molecular imaging revealed that SL AcHERV-triHPV in mice provided complete protection against vaginal challenge with HPV16, HPV18, and HPV58 pseudoviruses. These results support the potential of SL immunization using multivalent DNA vaccine in baculovirus nanovector for induction of mucosal, systemic, and cellular immune responses.

Microneedle‐Mediated Vaccine Delivery to the Oral Mucosa

“…The oral cavity is easily accessible, minimally invasive, contains rich lymphoid tissue, and it has a pH that is more favorable for biologics compared to the gastrointestinal tract. Additionally, evidence suggests that oral mucosal vaccine delivery elicits systemic humoral and cellular immune responses comparable to intramuscular vaccination, and enhances levels of mucosal antibody responses locally and at distal sites such as the nasal cavity and female reproductive tract . However, vaccine delivery to the oral cavity has been limited by a lack of appropriate dosage forms to address physical barriers such as salivary flow and barriers to immune activation such as the predisposition for oral mucosal immune cells to be tolerogenic.…”

“…Vaccine delivery to the sublingual and buccal mucosa can generate mucosal immune responses at distal sites including the urogenital tract, the respiratory tract, and the intestinal tract . A wide variety of systemic and mucosal immune responses have been induced by vaccine delivery to these sites (Table ).…”

“…Sublingual delivery resulted in tenfold lower serum IgG and IgA responses compared to intranasal delivery and insignificant mucosal IgA titers in the vaginal mucosa. In another study, plasmid DNA was incorporated into a nonreplicating baculovirus nanovector for sublingual delivery . This delivery strategy generated comparable serum IgG titers, CD4+ and CD8+ T cell responses to intramuscular delivery.…”

Technologies to Improve Immunization

“…576 To overcome the inherent mucosal tolerance for antigens, a variety of mucosal adjuvants have been studied. 576,[591][592][593][594] For example, mice sublingually immunized with influenza vaccine (hemagglutinin split vaccine) with a lipopolysaccharide adjuvant demonstrated both hemagglutinin-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with SC vaccination. 591 Two mucosal adjuvants-αgalactosylceramide, a potent stimulator of natural killer T cells, and cytosine phosphate guanine-oligodeoxynucleotide a Tolllike receptor-9 agonist-effectively increased gp140-specific serum IgG and vaginal IgA levels following SL vaccination in mice.…”

Advances Towards Painless Vaccination and Newer Modes of Vaccine Delivery

“…Many laboratories have documented the efficacy of sublingual immunization in inducing adequate immune response in experimental animal systems using a variety of antigens, including soluble proteins, inert particulate antigens (killed viruses, virus-like particles, bacterial extracts) as well as live-attenuated viruses [20]. Researchers have successfully demonstrated protection against H. pylori [21], HPV16, HPV18, and HPV58 pseudoviruses [22] by sublingual vaccination in animals. The sublingual mucosa is a promising vaccine delivery route for other respiratory pathogens including influenza virus, Respiratory Syncytial virus (RSV) and Severe Acute Respiratory Syndrome (SARS) virus [23].…”